Olanzapine-induced weight gain: lessons learned from developing rat models

Olanzapine is an effective and commonly prescribed antipsychotic drug, used for the treatment of schizophrenia and bipolar disorder. Unfortunately significant weight gain is a common side effect. In order to effectively address this side effect, it is crucial to gain insight into the underlying mechanisms. Therefore, this thesis describes the development of a number of rat models that were designed to determine the effects of olanzapine on different aspects of energy balance. In both short- and long-term experiments, we simultaneously examined effects of olanzapine on meal patterns, food preference, locomotor activity and body temperature in male rats. In these studies olanzapine affected energy expenditure by reducing locomotor activity and body core temperature. Concerning food intake, olanzapine caused an increase in average meal size accompanied by reduced meal frequency, without any clear effects on food preference. Thus the primary effect of olanzapine on feeding appears to be an impairment of the normal satiation process. Furthermore, with chronic administration, body composition of olanzapine-treated rats was altered, favoring adipose tissue over lean muscle mass, despite reductions in overall body weight gain. A different model was developed to investigate whether olanzapine alters motivation for palatable food. We found that olanzapine, in low doses, increased the motivation of rats to work for sucrose pellets under a progressive ratio schedule of reinforcement. Conversely, administration of the weight-loss drug sibutramine (a noradrenaline/serotonin reuptake inhibitor) dose-dependently decreased motivation in this paradigm. When co-administered, a sub-effective dose of sibutramine was able to prevent the increase in motivation olanzapine. This suggests that an increase in motivation for palatable food is likely to be a significant contributor to olanzapine-induced weight gain and that the ability of sibutramine to reduce this motivation for palatable food may play an important role in the efficacy of sibutramine as an add-on treatment to counteract olanzapine-induced weight gain. To further investigate how olanzapine impairs the satiation process, a model was developed in which olanzapine was administered acutely. In this model we determined the effect of olanzapine on post-prandial levels of leptin, insulin, ghrelin, cholecystokinin (CCK), glucagon-like peptide 1, peptide YY and amylin. Olanzapine did not affect the secretion of any of these hormones, except for post-prandial ghrelin levels, which were increased compared to controls. Olanzapine also caused a significant increase in pre-prandial ghrelin levels, whereas it failed to affect baseline ghrelin levels. Using a similar model, we also investigated the effect of olanzapine on the efficacy of CCK to reduce meal size. We found that olanzapine pre-treatment counteracted the reduction in meal size by CCK, although there was no significant interaction between treatments. Together, these data suggest that olanzapine may enhance meal size by selectively increasing meal-related ghrelin secretion, and by counteracting the effect of CCK. In the process of developing our different models, several technical issues arose with different modes of administration of olanzapine, which are described and discussed. To conclude, the main findings of this thesis are discussed in view of clinical observations and other studies using rat models.